Summary of work: The neuroanatomic and neurophysiologic underpinnings of age-associated cognitive and memory change remain unclear, as there are a limited number of studies of longitudinal brain changes in individuals without dementia. We are performing serial magnetic resonance imaging (MRI), including measures of vascular changes, positron emission tomography (PET), and neuropsychological assessments in participants from the Baltimore Longitudinal Study of Aging (BLSA) to investigate the neurobiological basis of memory change and cognitive impairment. These evaluations allow us to examine changes in brain structure and function which may be early predictors of cognitive change and impairment, including Alzheimer's disease (AD). We are continuing longitudinal testing of older participants and evaluating new participants, including MRI and concurrent neuropsychological assessments of participants less than 55 years old. For individuals aged 55 and older, we also currently perform a single PET measurement of CBF, followed by a PET scan using 11-C-Pittsburgh Compound B (PiB) to measure in vivo amyloid distribution. Our progress over the last year includes continued acquisition of new neuroimaging assessments as well as continued analysis of existing data and methods development. Approximately half of the neuroimaging study participants are enrolled in the BLSA autopsy program, and the integration of autopsy and imaging findings is an active area of investigation to gain a better understanding of factors that promote cognitive resilience in individuals who have amyloid pathology but do not show memory impairment. In addition, we are using neuroimaging tools to investigate modulators of cognitive and brain changes, including sex differences in brain aging, genetic risk factors, and the effects of sex steroid and other hormones. An understanding of these brain-behavior associations and early detection of accelerated brain changes that predict cognitive decline and impairment will be critical in identifying individuals likely to benefit from new interventions. Over the last year, we have published a number of papers from this study. Consistent with imaging findings at other centers and autopsy studies, we find that about 30 percent of cognitively normal older adults have detectable levels of amyloid in the brain. Our PiB studies have demonstrated that higher PiB levels in cognitively normal individuals are associated with greater decline over time in mental status and memory (Resnick et al, 2010) but PiB was not significantly associated with regional tissue loss in normal individuals (Driscoll et al, 2011). These studies also have revealed longitudinal increases in PiB retention in individuals with higher PiB retention at initial PiB assessment (Sojkova et al, 2011) and the concordance and discordance between in vivo amyloid imaging patterns and pathological ratings of amyloid plaques according to the CERAD classification for pathological diagnosis of AD (Sojkova et al, 2010). Our imaging-neuropathology analyses have highlighted difficulties in using standard neuropathological diagnosis for autopsy validation of PiB due to differences in regions examined under the standard CERAD assessment and the brain regions showing the earliest amyloid deposition on PiB imaging. We are using the spatial patterns of PiB binding (and MRI tissue loss and lesions) to guide more detailed autopsy analyses. In addition, we have investigated clusterin and other plasma protein concentrations and genetic risk in relation to PiB levels and patterns. Higher clusterin concentration in plasma at baseline neuroimaging assessment was associated with higher medial temporal PiB retention more than 10 years later (Thambisetty et al, 2010). In addition, we combined proteomics with in in vivo amyloid imaging to identify a panel of 18 2DGE plasma protein spots that discriminated between individuals with high and low brain A&#946;(Thambisetty et al, 2010). Mass spectrometry identified these proteins, many of which have established roles in A&#946;clearance, including a strong signal from apolipoprotein-E (ApoE). Plasma ApoE concentration was associated with increased A&#946;burden in the medial temporal lobe, most pronounced in the hippocampus and entorhinal cortex. APOE &#949;4 carriers also showed greater A&#946;levels in several brain regions relative to &#949;4 non-carriers. These results suggest that both peripheral concentration of ApoE protein and APOE genotype are related to early neuropathological changes in brain regions vulnerable to AD pathology even in the non-demented elderly. The data from this project also continue to be used for important methodological developments to enhance analysis of longitudinal neuroimaging data, including papers describing new approaches for skull-stripping on MRI (Carass et al., 2011), cluster analysis of imaging data for detection of a cluster-based measure of pathology that reflects the deviation of a subject's MR image from a normal (i.e. cognitively stable) state (Filipovych et al, 2011), and an extension of Biological Parametric Mapping to include robust regression and robust inference in the neuroimaging context of application of the general linear model (Xue et al, 2011).